We recently showed that the compound genotype KIR3DS1/HLA-B Bw4-80I confers protection against the development of AIDS defining opportunistic infections. Interestingly, no protection against the development of AIDS defining malignancies was observed. The double protection of this compound genotype in AIDS, along with the specificity of its effects is a novel finding and underscores the complex role of host immunogenetics against HIV/AIDS. Analysis of the KIR3DL1 data illustrates a primary role for multiple distinct combinations of KIR3DL1 and HLA-Bw4 in the innate immune response against HIV. Of note, highly-expressed, highly-inhibitory KIR3DL1 alleles strongly enhance protection conferred by Bw4-80I alleles. The data can be explained logically by a model in which greater dependency on the expression of specific KIR3DL1 + Bw4 receptor-ligand pairs for NK cell inhibition in the resting state results in more pronounced NK cell responses when that inhibition is abrogated in the face of infection. In collaboration with Drs. Steve Anderson and Dan McVicar we have demonstrated for the first time that KIR3DS1 is expressed on NK cells with a KIR3DS1 expressing NK cell subset highly represented within the peripheral NK cell compartment. The presence of a Z27dim DX9- peak in 53/64 individuals that represented 15 to 81 percent of NK cells was observed. Individual KIR genotyping correlated this observation with the presence of the KIR3DS1 allele. Furthermore, transfection of HEK293 cells with a KIR3DS1 expression construct confirmed the KIR3DS1 reactivity of Z27. Z27, but not DX9, was able to trigger NK cell degranulation and interferon gamma secretion in resting and/or IL 2 activated NK cells. Taken together, these data support the involvement of KIR3DS1 in HIV pathogenesis.